tbuckley/cabot-search huggingface dataset:
Predictors of resistance to trastuzumab deruxtecan (T-DXd) in esophagogastric adenocarcinoma (EGC).
Authors: Charlton Tsai, Joanne F. Chou, Tiago Biachi de Castria, Laura H. Tang, David H. Ilson, Geoffrey Yuyat Ku, Nikolaus Schultz, Marinela Capanu, Yelena Y. Janjigian, Steven Brad Maron
Journal: Journal of Clinical Oncology (2023)

e16024 Background: In DESTINY-Gastric01/02, T-DXd improved objective response rates (ORR) and overall survival (OS) relative to chemotherapy in patients (pts) with trastuzumab-refractory HER2+ EGC. We sought to identify clinicopathologic features that predict response and resistance to T-DXd, in a cohort from Memorial Sloan Kettering Cancer Center (MSKCC). Methods: Demographics of pts with HER2+ (HER2 IHC 3+ or IHC 2+/FISH+) advanced EGC at MSKCC treated with T-DXd in 2 nd line or later (2L+) from 2017 to 2022 were reviewed via the medical record. Progression-free survival (PFS) and OS were calculated from T-DXd initiation to event or last follow up. Univariate (UV) and multivariable (MV) analyses of PFS were performed using Cox proportional hazards models. Categorical comparisons used the χ 2 or Fisher’s exact test when subgroup n &lt; 5. Results: 57 pts received 2L+ T-DXd (25 2L, 18 3L, 14 4L+). Median age at treatment was 64.5 years and most pts were male (74%) and white (82%) with primary tumors in the esophagus/GE junction (72%) and HER2 IHC 3+ expression (82%). With median follow up of 12 months (mos), ORR was 49% with median PFS (mPFS) of 5.4 mos (95% CI 3.2 – 6.8) and median OS (mOS) of 13 mos (95% CI 8.5 – 19). Pts with HER2 IHC 2+ EGC had lower ORR (30% vs 53%, p = 0.3) and inferior PFS compared to IHC 3+ in UV analysis (HR 2.58, 95% CI 1.08 – 6.13 mos, p = 0.03). Pts with HER2 retesting (n = 22) within 1 mo prior to T-DXd had higher ORR (64% vs 40%, p = 0.08); HER2 IHC in 4 of these pts decreased from 3+ to 2+. Despite irinotecan (irino) ORR of 38% prior to T-DXd in 8 pts, only 1 (12%) had OR to T-DXd. Furthermore, only one of the 12 pts (8%) who received irino following T-DXd had OR to irino, despite T-DXd ORR of 42% among these pts. Irino-treated pts also had worse PFS on T-DXd (vs no prior irino, HR 4.91, 95% CI 2.09 – 11.5 mos, p &lt; 0.001). Prior checkpoint inhibition was not associated with PFS on T-DXd. In MV analysis, prior irino therapy remained significantly associated with progression/death (HR 4.12, 95% CI 1.63 – 10.4 mos, p = 0.003), and not HER2 IHC 2+ (vs 3+) nor 3L+ treatment (vs 2L). Additional correlations with genomic alterations will be presented. Conclusions: Consistent with DESTINY-Gastric trials, approximately half of pts with EGC at MSKCC had OR to T-DXd with mOS &gt; 1 year. However, our real-world findings suggesting lower ORR in patients with sequential T-DXd and irinotecan-containing therapy and those without pre-T-DXd HER2 IHC confirmation merit further validation in future studies.
Treatment failure with first line imatinib for patients with chronic myeloid leukaemia in Kenya vs high-income countries.
Authors: Angela Awino Mcligeyo, Nicolas Abinya, Sitna Ali Mwanzi, Peter Omondi Oyiro, Andrew Oluoch Odhiambo, Mohammed Shabbir Ezzi, Matilda Ong'ondi, Miriam Claire Mutebi, Mary Flaviane Nyangasi, Valerian Mwenda
Journal: Journal of Clinical Oncology (2023)

e19068 Background: Chronic Myeloid Leukemia (CML) occurs in all age groups but predominantly in adults. The disease pathogenesis is typified by the presence of BCR-ABL fusion protein coded for by BCR-ABL gene, a product of reciprocal translocation between the long arms of chromosomes 9 and 22 denoted: t(9;22)(q34;q11). This results in leukaemogenic aberrant tyrosine kinase activity. The clinical course is characterized by three phases namely – chronic stable phase, accelerated phase and acute (blastic phase). Imatinib mesylate, an inhibitor of BCR-ABL was approved for treatment of CML and revolutionized its treatment and outcome. There is however a failure rate on imatinib of about 15 % that is partially addressed by second- and third-line tyrosine kinase inhibitors. Methods: We retrospectively collected data on patients treated at the Glivec International Patient Assistance Program (GIPAP), later Max Access Solutions (MAS) clinics at the Nairobi Hospital. Patient demographics, date of diagnosis, disease phase, and date of commencement of imatinib were documented. Treatment failure/switch, and reason were also documented. Results: A total of 1347 patients were included. Mean age was 44.12 years, males were 748 (55.5%), females 599 ((44.5%). All except two (1345) were initiated on imatinib, 206 (15.3%) were switched to second-line therapy due to various reasons including 31(2.3%) due to adverse events, 148 (11%) treatment failure, 15 (1.1%) due to unspecified reasons and 1 due to drug stock-outs. Second line medications were given to 204 patients: 100 (49%) dasatinib, 50 (24.5%) bosutinib, 38 (18.6%) nilotinib, 16 (7.8%) ponatinib. Deaths or losses to follow-up were 181 (13.4%). Conclusions: Overall about 15% failed on imatinib first-line therapy, similar to the experience from high-income countries. The most preferred second-line TKI was dasatinib, based on availability and toxicity profile.
Genomic biomarker testing and treatment in advanced NSCLC: Practice patterns and barriers in a global survey of oncology point-of-care mobile app users.
Authors: Anne Jacobson, Eugene Pozniak, Kevin Dan Bambury, Eoin O'Carroll, Renita George, Giuseppe Luigi Banna
Journal: Journal of Clinical Oncology (2023)

e21004 Background: Appropriate molecular testing and oncogene-directed treatment planning are essential best practices for managing patients with advanced non-small cell lung cancer (aNSCLC) who are potential candidates for targeted therapy. Understanding real-world practices and challenges among oncology health care professionals (HCPs) is necessary to inform the development of digital tools and other initiatives that support optimal care. Methods: From 12/2022 to 01/2023, 142 HCPs who treat aNSCLC completed an online survey related to NSCLC genomic biomarker testing and treatment planning. Participants were recruited from a global cohort of HCPs who are active users of an oncology point-of-care mobile app following the launch of an NSCLC decision-support tool and educational intervention. Results: Participants included medical oncologists (87%), surgical oncologists (3%), pulmonologists (2%), and nurses (4%) from 62 countries. Most (72%) reported providing care for ≥5 pts/month with aNSCLC; 27.5% provide care for ≥20 pts/month. HCPs reported testing the following genomic biomarkers in 100%, 50-99%, 1-49%, and 0% of patients with aNSCLC, respectively: EGFR (44%, 23%, 27%, 4%), ALK (41%, 20%, 29%, 8%), ROS1 (32%, 19%, 23%, 22%), BRAF (23%, 20%, 23%, 31%), NTRK (12%, 14%, 22%, 47%), HER2 (11%, 17%, 27%, 42%), KRAS (23%, 15%, 25%, 33%), RET (13%, 13%, 25%, 44%), MET exon 14 (15%, 12%, 27%, 42%). Reported barriers varied in frequency (Table 1), with the most common involving biomarker test turnaround time. The majority of HCPs reported often or sometimes feeling that “results take too long,” and they (80%) and/or their patients (81%) are eager to start treatment. HCPs also commonly reported often or sometimes not being sure about which tests to order (45%), when to test (43%), which 1st-line therapy to select (45%), which 2nd- or later-line therapy to select (57%), and how to manage adverse events of oncogene-targeted therapy (50%). Conclusions: In current real-world practice, the majority of HCPs report suboptimal testing for targetable genomic alterations ( EGFR, ALK, ROS1, BRAF, NTRK, HER2, KRAS, RET, and MET exon 14) in patients with aNSCLC. Identified common barriers represent opportunities for future interventions to improve biomarker-directed NSCLC care. [Table: see text]
CBX-12-101: A first-in-human study of CBX-12, an alphalex peptide drug conjugate (PDC) in patients (pts) with advanced or metastatic solid tumors.
Authors: Ildefonso I Rodriguez Rivera, Navid Hafez, Anthony W. Tolcher, Patricia LoRusso, Sharon Wilks, Debu Tripathy, Michelle Gara, Paul Pearson, Arthur P. DeCillis, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2023)

3087 Background: Tumor-targeted drug delivery technologies are urgently needed to overcome conventional chemotherapy’s lack of tumor selectivity. Alphalex conjugates, which contain a pH-low insertion peptide (pHLIP), a linker and a payload, are designed to overcome this lack of selectivity. Unlike antibody drug conjugates, alphalex PDCs target tumors in an antigen-agnostic manner. At pH ≥7.0, the peptide is unstructured. In the low-pH tumor microenvironment the peptide forms an alpha helix and inserts directionally into the tumor cell membrane delivering the linker and payload intracellularly where the linker is cleaved releasing the payload in the cytosol. CBX-12 consists of the pH-sensitive peptide, a self-immolating linker, and the topoisomerase 1 (TOP1) inhibitor exatecan. Methods: In this Phase 1 trial, cohorts of pts were treated with escalating doses of CBX-12 in a 3 + 3 design on three dosing schedules: daily x 5 every 3 weeks, daily x 3 every 3 weeks or once weekly. The primary objectives are safety, tolerability and to determine the MTD and/or RP2D. Secondary and exploratory objectives include evaluation of plasma PK of CBX-12 and exatecan, anti-tumor activity per RECIST v1.1, and measurement of anti-drug antibodies. Results: As of 26 Jan 2023, 42 pts have been treated on three schedules. The most frequent treatment-related AEs (TRAEs) were anaemia (42.9%), nausea (38.1%), fatigue (33.3%), ANC and WBC decreased (33.3% each), vomiting (26.2%), diarrhoea (23.8%) and thrombocytopenia (19.0%). The most frequent Gr3/4 TRAEs were ANC decreased (28.6%), anemia (23.8%), WBC decrease (16.7%), thrombocytopenia (14.3%). Dose limiting toxicity was observed in 6 pts: myelosuppression (6 pts) febrile neutropenia (2 pts), and sepsis (2 pts). Responses were observed in 2 of 9 pts with ovarian cancer and 2 of 8 with breast cancer. The MTD on the daily x 3 schedule is 45mg/m 2 . Dose evaluation continues on the weekly schedule. Conclusions: In this FIH study of a pH-targeting alphalex PDC, CBX-12 demonstrated single-agent antitumor activity including 4 responses with the dominant toxicity of myelosuppression. Phase 2 expansion cohorts are planned in pts with platinum-resistant ovarian cancer and hormone-receptor positive, HER2 negative breast cancer. Clinical trial information: NCT04902872 .
Prognostic impact of PSA nadir (n) ≥0.1 ng/mL within 6 months (m) after completion of radiotherapy (RT) for localized prostate cancer (PCa): An individual patient-data (IPD) analysis of randomized trials from the ICECAP collaborative.
Authors: Praful Ravi, Lucia Kwak, John Armstrong, Veronique Beckendorf, Joseph Chin, Anthony Victor D'Amico, David P. Dearnaley, James William Denham, Savino Mauro Di Stasi, Silke Gillessen, Himanshu Lukka, Nicolas Mottet Auselo, Pascal Pommier, Wendy Seiferheld, Matthew R. Sydes, Bertrand F. Tombal, Almudena Zapatero, Meredith M. Regan, Wanling Xie, Christopher Sweeney
Journal: Journal of Clinical Oncology (2023)

5002 Background: RT + androgen deprivation therapy (ADT) is a standard of care in treatment of intermediate- and high-risk localized PCa. Identification of early surrogate measures for long-term outcome measures such as PCa-specific survival (PCSS), metastasis-free survival (MFS) and overall survival (OS) could expedite development of new systemic therapies added to RT/ADT while potentially identifying patients (pts) for therapy (de)escalation. Methods: IPD from the RT+/-ADT trials in the ICECAP repository with evaluable PSA follow-up were eligible for inclusion. Pts were grouped based on their trial-allocated treatment: RT alone, RT+stADT (short-term ADT: 3-6m), RT+ltADT (long-term ADT: 18-36m). PSAn was defined as the lowest PSA recorded within 6m after RT completion. A 12m landmark analysis for PCSS, MFS and OS was performed to account for guarantee-time bias. Multivariable Cox proportional hazards regression was used to estimate associations of PSAn &lt; or ≥0.1ng/mL with MFS and OS, and a multivariable Fine and Gray distribution used for PCSS to account for competing risk of non-PCa deaths. Models were adjusted for age, ECOG performance status, clinical T stage, Gleason score and PSA at randomization. Results: 10,415 pts from 16 RCTs were included: 2629 (25%) allocated to RT, 6033 (58%) to RT+stADT, and 1753 (17%) to RT+ltADT. Median follow-up was 10.1years (yrs). 2339 (98%), 4756 (84%) and 1258 (77%) of patients allocated to RT, RT+stADT and RT+ltADT respectively achieved a PSAn ≥0.1ng/mL within 6m after RT completion. After adjustment, PSAn ≥0.1ng/mL was associated with poorer PCSS, MFS and OS in pts allocated to RT+stADT (PCSS hazard ratio [HR] = 1.97 [95% CI 1.52-2.92], MFS HR = 1.27 [1.12-1.44], OS HR = 1.26 [1.11-1.44]) and RT+ltADT (PCSS HR = 1.97 [1.11-3.49], MFS HR = 1.58 [1.27-1.96], OS HR = 1.59 [1.27-1.99]). A weaker association was noted in pts allocated to RT (PCSS HR = 1.82 [0.51-6.49], MFS HR = 2.23 [1.20-4.14], OS HR = 1.72 [0.97-3.05]). Table shows 5-yr MFS, 10-yr PCSS and 10-yr OS based on PSAn within 6m after RT completion. Conclusions: PSAn ≥0.1ng/mL within 6 mths after RT completion was strongly prognostic for PCSS, MFS and OS in pts receiving RT+ADT for localized PCa in this IPD analysis of &gt; 10,000 patients. This could be used as an early signal-seeking endpoint in trials evaluating novel systemic therapies with RT + ADT and to help identify pts for therapy (de)escalation trials. [Table: see text]
A phase ll study on the neoadjuvant treatment of resectable high-risk soft tissue sarcoma with anlotinib and doxorubicin.
Authors: Yao Weitao, Jiaqiang Wang, Peng Zhang, Xin Wang, Zhiyong Liu, Xinhui Du, Bangmin Wang, Zhehuang Li, Guancong Liu
Journal: Journal of Clinical Oncology (2023)

e23542 Background: Anthracycline and ifosfomide-based chemotherapy is the main neoadjuvant treatment option for resectable high-risk STS with severe myelosuppression and other side effects. Anlotinib has been approved as second-line treatment for most of advanced STS by the Chinese agency. This study was conducted to evaluate the efficacy and safety of anlotinib in combination with doxorubicin in the neoadjuvant treatment of patients with resectable high-risk STS to reduce the toxicity of chemotherapy. Methods: This is a single-center, prospective study. Eligible patients were those ≥18years old, ECOG performance state of 0-1, with histologically conﬁrmed locally resectable high-risk STS. All patients received a preoperative combination of anlotinib (12mg once daily, on for 2 weeks, off for 1 week) and doxorubicin (75mg /m2, IV, D1-2, every 3 weeks) .The combination treatment was repeated 2 to 3 cycles before operation. The primary endpoint was objective response rate (ORR), and the second endpoints were Disease control rate (DCR), and side eﬀects. Results: Between December 2020 and December 2022, 13 patients were evaluated, including 4 synovial sarcoma, 3 undifferentiated sarcoma, 3 spindle cell sarcoma, 2 liposarcoma, 1 angiosarcoma. The median age was 35 years. 1 patients (7.69%) achieved a conﬁrmed partial response (PR) and 7 (53.85%) had stable disease (SD). The ORR and DCR were 7.69% and 61.54% respectively. All patients underwent marginal or extensive excision of the tumor and none underwent amputation. Most of Treatment-related adverse events included neutropenia 5 (38.46%), hypothyroidism 3 (23.08%), anemia 2(15.38%). Three patients experienced grade 3 or 4 adverse events, neutropenia (1/13, 7.69%) and tumor hemorrhage (2/13, 15.38%). No wound complications such as infection, delayed healing or haematoma occurred. Conclusions: This study suggested that the combination of anlotinib and doxorubicin might be a option for neoadjuvant therapy for patients with resectable high-risk STS due to the anti-tumor activity and acceptable toxicity.
Remote delivery of a mindfulness-based intervention to decrease stress levels and promote coping among health-care workers during the COVID-19 pandemic.
Authors: Joelle Antoine Helou, Aisling S Barry, Philip Ye, Fei-Fei Liu, Anet Julius, Daniel Letourneau, Philip Wong, Laura A. Dawson, Mary Elliott
Journal: Journal of Clinical Oncology (2023)

11007 Background: The COVID-19 pandemic has caused significant stress amongst everyone around the world. Healthcare workers (HCW) in particular, experience substantial stress in these challenging environments. In an effort to find supportive interventions for radiation oncology providers, while respecting the requirements of physical distancing, we proposed the remote delivery of a mindfulness-based intervention (MBI). The primary aim of this study is to determine the association of this intervention with a reduction of perceived stress. Secondary aims are to evaluate the impact on coping and burnout amongst HCW in the Radiation Program (RP). Methods: This is a single-centre, single-arm, pilot study. All HCW associated with the RP were eligible. This was a voluntary effort. The intervention - manualized, mindfulness-based group for HCW, entitled Mindfulness-Based Resilience and Well-Being Training, consisted of four 1-hour sessions per week for 4 weeks. From Nov 2020 to Dec 2021, 6 consecutive closed groups MBI were delivered remotely using Zoom. Each group consisted of 5-12 participants and one professional with a background in mindfulness facilitation. The Perceived Stress Scale (PSS), The Maslach Burnout Inventory and the BriefCOPE questionnaire were collected pre-intervention, and at 1, 4 and 12 weeks post-intervention. Linear mixed effect models with a random intercept to account for the repeated measures were used to assess the change of outcomes over time. Results: Amongst 43 HCWs who expressed initial interest, 33 completed the study. At 1-, 4- and 12-weeks post-intervention 25, 24 and 21 participants provided completed questionnaires respectively. Time constraint was the main reason for withdrawal and missing data. There was a significant decrease in perceived stress at week 1, 4 and 12 when compared to baseline [mean baseline PSS score: 22.5 (SD = 4.6), week 1: 18.4 (4.9), p= 0.002, week 4: 16.8 (6.5), p&lt; 0.001, week 12: 16.3 (6.8), p&lt; 0.001]. Overall, 7 (21%) participants reported high PSS (27-40) at baseline while none reported high levels at 1 and 12 weeks. Problem focused coping( p= 0.02), and active coping ( p= 0.009) were significantly higher at 1 week but not at 4 and 12 weeks. Conclusions: The remote delivery of a MBI is feasible and effective to reduce perceived stress levels and to promote coping across HCWs. These findings need to be validated in a larger cohort. Time was a major constraint preventing the participation of interested HCWs. It would be extremely valuable for departments to support such interventions and programs to help HCWs cultivate skills to meet the demands related to working in healthcare environments throughout and beyond this crisis.
GUIDE: A randomized non-comparative phase II trial of biomarker-driven intermittent docetaxel versus standard-of-care docetaxel in metastatic castration-resistant prostate cancer (ANZUP 1903).
Authors: Ciara Conduit, Blossom Mak, Wenjia Qu, Theresa Yeung, Mathias Bressel, Thomas Cusick, Haryana M. Dhillon, Richard De Abreu Lourenço, Craig Underhill, Javier Torres, Megan Crumbaker, Florian Honeyball, Anthony Linton, Sanjeev Sewak, Nguyen Minh Hieu Chau, Ray Allen, Ian D. Davis, Susan J. Clark, Lisa Horvath, Kate Lynette Mahon
Journal: Journal of Clinical Oncology (2023)

TPS5099 Background: Docetaxel improves survival in people with metastatic castration resistant prostate cancer (CRPC) but is associated with toxicities which impact tolerability, particularly for patients who may be older and often with multiple co-morbidities. Biomarker-driven de-escalation of docetaxel chemotherapy may allow improved balance of cancer control and quality of life against toxicity. In patients with metastatic CRPC receiving docetaxel, a reduction to undetectable levels in circulating promoter methylated glutathione S-transferase Pi-1 ( mGSTP1) DNA after 2 cycles of chemotherapy is associated with improved overall survival 1 . This study aims to determine the efficacy and safety of intermittent docetaxel chemotherapy guided by the presence or absence of circulating mGSTP1 DNA in patients with metastatic CRPC. Methods: GUIDE (NCT04918810) is a randomized, two-arm, non-comparative phase 2 trial recruiting 120 patients at eight Australian centres. Patients with Prostate Cancer Working Group-3 defined metastatic CRPC who are commencing docetaxel 75mg/m 2 q3w will be pre-screened for detectable mGSTP1 at baseline +/- following two cycles of treatment. Those with detectable plasma mGSTP1 at baseline that becomes undetectable after two cycles of chemotherapy will be eligible for GUIDE. Prior to Cycle 4 of docetaxel, these patients are randomized 2:1 to one of two treatment arms: Arm A (cease docetaxel and reinstitute if mGSTP1 becomes detectable) or Arm B (continue docetaxel 75mg/m 2 q3w in accordance with clinician’s usual practice) (Figure 1). The primary endpoint is radiographic progression-free survival (rPFS). Secondary endpoints include time on treatment holidays, safety, patient-reported outcomes, overall survival, health resource use and cost associated with treatment. This study is powered to detect a rPFS curve with at least 50% rPFS at 12 months using a one-sided log-rank test with 2.5% alpha and 90% power. 3 of planned 120 patients have been enrolled. This novel study is the first to prospectively test the clinical utility of a circulating epigenetic biomarker ( mGSTP1) in clinical decision-making in prostate cancer, building upon existing data supporting analytical and clinical validity. We anticipate that this novel biomarker will safely guide treatment de-escalation and improve the quality of survival for a group of patients with metastatic CRPC. Clinical trial information: NCT04918810 .